8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions

ABSTRACT

Disclosed are substituted xanthines of the formula 
                         
wherein R is defined as in claim  1 , the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

APPLICATION DATA

This application claims the benefit under 35 USC 119(a) of GermanApplication No. 10 2004 008 112, filed Feb. 18, 2004, German PatentApplication No. 10 2004 012 921, filed Mar. 17, 2004, and German PatentApplication No. 10 2004 032 263, filed Jul. 3, 2004, which applicationsare incorporated herein by reference in their entirety. This applicationclaims the benefit under 35 USC 119(e) of U.S. Provisional ApplicationSer. No. 60/551,108, filed on Mar. 8, 2004, and U.S. ProvisionalApplication Ser. No. 60/562,573, filed on Apr. 15, 2004, whichapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to new substituted xanthines of generalformula

the tautomers, the enantiomers, the stereoisomers, the mixtures thereof,and the salts thereof, particularly the physiologically acceptable saltsthereof, with inorganic or organic acids that have valuablepharmacological properties, particularly an inhibiting effect, on theactivity of the enzyme dipeptidylpeptidase-IV (DPP-IV), the preparationthereof, the use thereof for preventing or treating illnesses orconditions connected with an increased DPP-IV activity or capable ofbeing prevented or alleviated by reducing the DPP-IV activity,particularly type I or type II diabetes mellitus, the pharmaceuticalcompositions containing a compound of general formula (I) or aphysiologically acceptable salt thereof, and processes for thepreparation thereof.

Xanthine derivatives with an inhibiting effect on DPP-IV are alreadyknown from WO 02/068420, WO 02/02560, WO 03/004496, WO 03/024965, WO04/018468, WO 04/048379, JP 2003300977, and EP 1 338 595, whichapplications and other applications corresponding thereto areincorporated herein by reference in their entireties.

In the above formula I:

-   R denotes a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,    2,6-difluoro-benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl,    3-chlorobenzyl, or 4-chlorobenzyl group,-   a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl, or    4-trifluoromethyl-benzyl group,-   a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,-   a 2-cyanobenzyl, 3-cyanobenzyl, or 4-cyanobenzyl group,-   a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl,    2-trifluoromethyl-4-cyano-benzyl, 3-nitro-4-cyano-benzyl,    2-cyano-3-methoxy-benzyl, 2-cyano-4-methoxy-benzyl,    2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl,    2-cyano-5-fluoro-benzyl, 2-cyano-6-fluoro-benzyl,    3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro-benzyl,    2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl,    2-chloro-4-cyano-benzyl, or 2-cyano-4-bromobenzyl group,-   a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl,    2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl,    2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl,    3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl, or    3,4-dimethoxy-6-fluoro-benzyl group,-   a (benzo[1,3]dioxol-5-yl)methyl group,-   a [(4-cyano-benzo[1,3]dioxol-5-yl)methyl group,-   a 2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl,    2-(3-cyclopropylmethoxy-phenyl)-2-oxo-ethyl, or    2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl group,-   a 2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl or    2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl group,-   a (3-cyano-naphthalen-1-yl)methyl,    (1,4-dicyano-naphthalen-2-yl)methyl, or    (2,4-dimethoxy-naphthalen-1-yl)methyl group,-   a (furan-2-yl)methyl, (furan-3-yl)methyl,    (5-bromo-furan-2-yl)methyl, (5-methyl-furan-2-yl)methyl,    (5-cyano-furan-2-yl)methyl, or (5-methoxycarbonyl-furan-2-yl)methyl    group,-   a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or    (5-methoxy-pyridin-2-yl)methyl group,-   a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl,    (5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl,    (4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl,    (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl,    (5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl, or    (5-cyano-6-methoxy-pyridin-2-yl)methyl group,-   a (6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl    group,-   a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or    (4,6-dimethyl-pyrimidin-2-yl)methyl group,-   a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl    group,-   a [(1-methyl-1H-benzotriazol-5-yl)methyl] group,-   a (6-fluoro-quinolin-2-yl)methyl, (7-fluoro-quinolin-2-yl)methyl,    (2-methyl-quinolin-4-yl)methyl, (3-cyano-quinolin-2-yl)methyl,    (3-cyano-4-methyl-quinolin-2-yl)methyl,    (4-cyano-quinolin-2-yl)methyl, (5-cyano-quinolin-2-yl)methyl,    (8-cyano-quinolin-2-yl)methyl, (6-amino-quinolin-2-yl)methyl,    (8-amino-quinolin-2-yl)methyl, (4-methoxy-quinolin-2-yl)methyl,    (6-methoxy-quinolin-2-yl)methyl,    (6,7-dimethoxy-quinolin-2-yl)methyl, or    (8-cyano-quinolin-7-yl)methyl group,-   a (1-cyano-isoquinolin-3-yl)methyl,    (4-cyano-isoquinolin-1-yl)methyl-(4-cyano-isoquinolin-3-yl)methyl,    or [(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl group,-   a (quinazolin-6-yl)methyl, (quinazolin-7-yl)methyl,    (2-methyl-quinazolin-4-yl)methyl,    (4,5-dimethyl-quinazolin-2-yl)methyl,    (4-ethyl-quinazolin-2-yl)methyl,    (4-cyclopropyl-quinazolin-2-yl)methyl,    (2-phenyl-quinazolin-4-yl)methyl, (4-cyano-quinazolin-2-yl)methyl,    (4-phenylamino-quinazolin-2-yl)methyl, or    (4-benzylamino-quinazolin-2-yl)methyl group,-   a (quinoxalin-5-yl)methyl-(quinoxalin-6-yl)methyl or    (2,3-dimethyl-quinoxalin-6-yl)methyl group, or-   a ([1,5]naphthyridin-3-yl)methyl group,-   the tautomers, enantiomers, diastereomers, and the mixtures and the    salts thereof.

Preferred are compounds of general formula Ia:

wherein R is as hereinbefore defined, as well as their tautomers andsalts.

Also preferred are compounds of general formula Ib

wherein R is as hereinbefore defined, as well as their tautomers andsalts.

According to the invention the compounds of general formula I areobtained by methods known, per se, for example, by the followingmethods:

a) reacting a compound of general formula II

whereinR is as hereinbefore defined andZ¹ denotes a leaving group, such as a halogen atom, a substitutedhydroxy, mercapto, sulfinyl, sulfonyl or sulfonyloxy group, such as achlorine or bromine atom, a methanesulfonyl, or methanesulfonyloxygroup, with 3-aminopiperidine, the enantiomers or the salts thereof.

The reaction is expediently carried out in a solvent, such asisopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide,dimethylsulfoxide, ethyleneglycol monomethylether, ethyleneglycoldiethylether, or sulfolane, optionally in the presence of an inorganicor tertiary organic base, e.g., sodium carbonate, potassium carbonate,or potassium hydroxide, a tertiary organic base, e.g., triethylamine, orin the presence of N-ethyl-diisopropylamine (Hünig base), while theseorganic bases may simultaneously also serve as solvent, and optionallyin the presence of a reaction accelerator, such as an alkali metalhalide or a palladium-based catalyst at temperatures between −20° C. and180° C., but preferably at temperatures between −10° C. and 120° C. Thereaction may, however, also be carried out without solvent or in anexcess of the 3-aminopiperidine.

b) deprotecting a compound of general formula III

wherein R is as hereinbefore defined.

The tert.-butyloxycarbonyl group is preferably cleaved by treating withan acid, such as trifluoroacetic acid or hydrochloric acid or bytreating with bromotrimethylsilane or iodotrimethylsilane, optionallyusing a solvent, such as methylene chloride, ethyl acetate, dioxane,methanol, isopropanol, or diethyl ether at temperatures between 0° C.and 80° C.

In the reactions described hereinbefore, any reactive groups present,such as amino, alkylamino, or imino groups, may be protected during thereaction by conventional protecting groups that are cleaved again afterthe reaction.

For example, a protecting group for an amino, alkylamino, or imino groupmay be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or2,4-dimethoxybenzyl group, and additionally, for the amino group, aphthalyl group.

Any protecting group used is optionally, subsequently cleaved, forexample, by hydrolysis in an aqueous solvent, e.g., in water,isopropanol/water, acetic acid/water, tetrahydrofuran/water, ordioxane/water, in the presence of an acid, such as trifluoroacetic acid,hydrochloric acid, or sulfuric acid, or in the presence of an alkalimetal base, such as sodium hydroxide or potassium hydroxide, oraprotically, e.g., in the presence of iodotrimethylsilane, attemperatures between 0° C. and 120° C., preferably at temperaturesbetween 10° C. and 100° C.

However, a benzyl, methoxybenzyl, or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g., with hydrogen in the presence ofa catalyst, such as palladium/charcoal, in a suitable solvent, such asmethanol, ethanol, ethyl acetate, or glacial acetic acid, optionallywith the addition of an acid, such as hydrochloric acid, at temperaturesbetween 0° C. and 100° C., but preferably at ambient temperaturesbetween 20° C. and 60° C., and at a hydrogen pressure of 1 to 7 bar, butpreferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl group ispreferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert.-butyloxycarbonyl group is preferably cleaved by treating with anacid, such as trifluoroacetic acid or hydrochloric acid, or by treatingwith iodotrimethylsilane, optionally using a solvent, such as methylenechloride, dioxane, methanol, or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acid,such as hydrochloric acid, optionally in the presence of a solvent, suchas acetic acid, at temperatures between 50° C. and 120° C., or bytreating with sodium hydroxide solution, optionally in the presence of asolvent, such as tetrahydrofuran, at temperatures between 0° C. and 50°C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine, such as methylamine, ethylamine, ethanolamine, orn-butylamine, in a solvent, such as methanol, ethanol, isopropanol,toluene/water, or dioxane, at temperatures between 20° C. and 50° C.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be separated bychromatography into their cis and trans isomers, the compounds ofgeneral formula I obtained that occur as racemates may be separated bymethods known, per se, (cf. Allinger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971), into their opticalenantiomers, and compounds of general formula I with at least 2asymmetric carbon atoms may be resolved into their diastereomers on thebasis of their physical-chemical differences using methods known, perse, e.g., by chromatography and/or fractional crystallisation, and, ifthese compounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases, or by recrystallisation from an optically active solvent, or byreacting with an optically active substance that forms salts orderivatives, such as, e.g., esters or amides with the racemic compound,particularly acids, and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g., on the basis of their differences in solubility, whereasthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are, e.g., the D- and L-forms of tartaric acid, ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinicacid. An optically active alcohol may be, for example, (+) or(−)-menthol and an optically active acyl group in amides, for example,may be a (+)- or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained may be converted intothe salts thereof, particularly, for pharmaceutical use, into thephysiologically acceptable salts, with inorganic or organic acids. Acidsthat may be used for this purpose include, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoricacid, fumaric acid, succinic acid, lactic acid, citric acid, tartaricacid, or maleic acid.

The compounds of general formulae II and III used as starting compoundsare either known from the literature or may be prepared by methods knownfrom the literature (see Examples I to XXV).

As already mentioned hereinbefore, the compounds of general formula Iaccording to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on the enzyme DPP-IV.

The biological properties of the new compounds were investigated asfollows:

The ability of the substances and their corresponding salts to inhibitthe DPP-IV activity can be demonstrated in an experiment in which anextract of the human colon carcinoma cell line Caco-2 is used as the DPPIV source. The differentiation of the cells in order to induce theDPP-IV expression was carried out in accordance with the description byReiher et al. in an article entitled “Increased expression of intestinalcell line Caco-2” that appeared in Proc. Natl. Acad. Sci. Vol. 90, pp.5757-5761 (1993). The cell extract was obtained from cells solubilizedin a buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 t.i.u. aprotinin, 0.5%Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4°C. (to remove cell debris).

The DPP-IV assay was carried out as follows:

50 μl of substrate solution (AFC; AFC isamido-4-trifluoromethylcoumarin), final concentration 100 μM, was placedin black microtitre plates. 20 μl of assay buffer (final concentrations50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) was pipetted therein. Thereaction was started by the addition of 30 μl of solubilized Caco-2protein (final concentration 0.14 μg of protein per well). The testsubstances under investigation were typically added prediluted to 20 μl,while the volume of assay buffer was then reduced accordingly. Thereaction was carried out at ambient temperature, the incubation periodwas 60 minutes. Then the fluorescence was measured in a Victor 1420Multilabel Counter, with the excitation wavelength at 405 nm and theemission wavelength at 535 nm. Dummy values (corresponding to 0%activity) were obtained in mixtures with no Caco-2 protein (volumereplaced by assay buffer), control values (corresponding to 100%activity) were obtained in mixtures without any added substance. Thepotency of the test substances in question, expressed as IC₅₀ values,were calculated from dosage/activity curves consisting of 11 measuredpoints in each case. The following results were obtained:

Compound DPP IV inhibition (Example No.) IC₅₀ [nM] 1 6 1(3) 6 1(4) 91(6) 2 1(7) 5 1(12) 2 1(21) 2 1(26) 2 1(30) 2 1(31) 3 1(38) 1 1(39) 2

The compounds prepared according to the invention are well tolerated, asno toxic side effects could be detected in rats after the oraladministration of 10 mg/kg of the compound of Example 1(30), forexample.

In view of their ability to inhibit DPP-IV activity, the compounds ofgeneral formula I according to the invention and the correspondingpharmaceutically acceptable salts thereof are suitable for influencingany conditions or diseases which can be affected by the inhibition ofthe DPP-IV activity. It is therefore to be expected that the compoundsaccording to the invention will be suitable for the prevention ortreatment of diseases or conditions such as type I and type II diabetesmellitus, pre-diabetes, reduced glucose tolerance or changes in thefasting blood sugar, diabetic complications (e.g., retinopathy,nephropathy, or neuropathies), metabolic acidosis or ketosis, reactivehypoglycemia, insulin resistance, metabolic syndrome, dyslipidemias ofvarious origins, arthritis, atherosclerosis and related diseases,obesity, allograft transplantation, and osteoporosis caused bycalcitonin. In addition, these substances are suitable for preventingB-cell degeneration, such as, e.g., apoptosis or necrosis of pancreaticB-cells. The substances are also suitable for improving or restoring thefunction of pancreatic cells and additionally increasing the size andnumber of pancreatic B-cells. Additionally, on the basis of the role ofthe glucagon-like peptides, such as, e.g., GLP-1 and GLP-2 and theirlink with DPP-IV inhibition, it is expected that the compounds accordingto the invention will be suitable for achieving, inter alla, a sedativeor tranquillising effect, as well as having a favorable effect oncatabolic states after operations or hormonal stress responses orpossibly reducing mortality and morbidity after myocardial infarct.Moreover, they are suitable for treating any conditions connected withthe effects mentioned above and mediated by GLP-1 or GLP-2. Thecompounds according to the invention may also be used as diuretics orantihypertensives and are suitable for preventing and treating acutekidney failure. The compounds according to the invention may also beused to treat inflammatory complaints of the respiratory tract. They arealso suitable for preventing and treating chronic inflammatory boweldiseases, such as, e.g., irritable bowel syndrome (IBS), Crohn'sdisease, or ulcerative colitis, and also pancreatitis. It is alsoexpected that they can be used for all kinds of injury or damage to thegastrointestinal tract such as may occur in colitis and enteritis, forexample. Moreover, it is expected that DPP-IV inhibitors and hence thecompounds according to the invention can be used to treat infertility orto improve fertility in humans or mammals, particularly if theinfertility is connected with insulin resistance or with polycysticovary syndrome. On the other hand, these substances are suitable forinfluencing sperm motility and are thus suitable for use as malecontraceptives. In addition, the substances are suitable for treatinggrowth hormone deficiencies connected with restricted growth, and mayreasonably be used for all indications for which growth hormone may beused. The compounds according to the invention are also suitable, on thebasis of their inhibitory effect on DPP-IV, for treating variousautoimmune diseases such as, e.g., rheumatoid arthritis, multiplesclerosis, thyroiditis, and Basedow's disease, etc. They may also beused to treat viral diseases and also, for example, in HIV infections,for stimulating blood production, in benign prostatic hyperplasia,gingivitis, as well as for the treatment of neuronal defects andneurodegenerative diseases, such as Alzheimer's disease, for example.The compounds described may also be used for the treatment of tumors,particularly for modifying tumor invasion and also metastasisation;examples here are their use in treating T-cell lymphomas, acutelymphoblastic leukemia, cell-based pancreatic carcinomas, basal cellcarcinomas, or breast cancers. Other indications are stroke, ischemia ofvarious origins, Parkinson's disease, and migraine. In addition, furtherindications include follicular and epidermal hyperkeratoses, increasedkeratinocyte proliferation, psoriasis, encephalomyelitis,glomerulonephritis, lipodystrophies, as well as psychosomatic,depressive, and neuropsychiatric diseases of all kinds.

The compounds according to the invention may also be used in conjunctionwith other active substances. Suitable therapeutic agents for suchcombinations include, for example, antidiabetic agents, such asmetformin, sulfonylureas (e.g., glibenclamid, tolbutamide, glimepiride),nateglinide, repaglinide, thiazolidinediones (e.g., rosiglitazone,pioglitazone), PPAR-gamma agonists (e.g., GI 262570) and antagonists,PPAR-gamma/alpha modulators (e.g., KRP 297), PPAR-gamma/alpha/deltamodulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors,SMT3 receptor agonists, 11β-HSD inhibitors, FGF19 agonists or mimetics,alpha-glucosidase inhibitors (e.g., acarbose, voglibose), other DPP-IVinhibitors, alpha2 antagonists, insulin and insulin analogues, GLP-1 andGLP-1 analogues (e.g., exendin-4), or amylin. Also, combinations withSGLT2 inhibitors, such as T-1095 or KGT-1251 (869682), inhibitors ofprotein tyrosine phosphatase 1, substances which influence deregulatedglucose production in the liver, such as, e.g., inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol-pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, lipid lowering agents, such as HMG-CoA-reductaseinhibitors (e.g., simvastatin, atorvastatin), fibrates (e.g.,bezafibrate, fenofibrate), nicotinic acid and its derivatives,PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g.,avasimibe), or cholesterol absorption inhibitors, such as, for example,ezetimibe, bile acid-binding substances, such as, for example,cholestyramine, inhibitors of ileac bile acid transport, HDL-raisingcompounds, such as, for example, inhibitors of CETP, or regulators ofABC1 or LXRalpha antagonists, LXRbeta agonists or LXRalpha/betaregulators, or active substances for the treatment of obesity, such ase.g., sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine,antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists,MC4 receptor agonists, NPY5 or NPY2 antagonists, or β₃-agonists, such asSB-418790 or AD-9677, as well as agonists of the 5HT2c receptor.

It is also possible to combine the compounds with drugs for treatinghigh blood pressure, such as, e.g., all antagonists or ACE inhibitors,diuretics, β-blockers, Ca-antagonists, etc., or combinations thereof.

The dosage required to achieve such an effect is expediently, byintravenous route, 1 to 100 mg, preferably 1 to 30 mg, and by oral route1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day.For this purpose, the compounds of formula I prepared according to theinvention, optionally combined with other active substances, may beincorporated together with one or more inert conventional carriersand/or diluents, e.g., with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose, or fatty substances, suchas hard fat or suitable mixtures thereof, into conventional galenicpreparations, such as plain or coated tablets, capsules, powders,suspensions, or suppositories.

The Examples that follow are intended to illustrate the invention:

Preparation of the Starting Compounds

EXAMPLE I1-[(4-phenylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

A mixture of 416 mg3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthineand 456 mg cesium carbonate in 4 ml N,N-dimethylformamide is stirred for10 minutes at 80° C., then 324 mg2-chloromethyl-4-phenylamino-quinazoline are added and the reactionmixture is stirred for two hours at 80° C. Then another 50 mg cesiumcarbonate and 50 mg chloromethyl-4-phenylamino-quinazoline are added andthe mixture is stirred for a further 1.5 hours at 80° C. Then thesolvent is distilled off and the residue is distributed between waterand ethyl acetate. The organic phase is washed with dilute citric acid,water and saturated sodium chloride solution, dried over magnesiumsulfate and evaporated down. The crude product is purified bychromatography over a silica gel column with ethyl acetate/petroleumether (8:2 to 10:0) as eluant.

Yield: 425 mg (65% of theory)

R_(f) value: 0.33 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=650 [M+H]⁺

The following compounds are obtained analogously to Example I:

-   (1)    1-[(4-benzylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.20 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=664 [M+H]⁺

-   (2)    1-[(2-methyl-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=572 [M+H]⁺

-   (3)    1-[(3-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.67 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=582 [M+H]⁺

-   (4)    1-[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=635 [M+H]⁺

-   (5)    1-[(4-cyano-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (6)    1-[(4-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (7)    1-[2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=591 [M+H]⁺

-   (8)    1-[2-(3-cyclopropylmethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.65 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=605 [M+H]⁺

-   (9)    1-[2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.85 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=605 [M+H]⁺

-   (10)    1-[(1-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (11)    1-[(2,4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=617 [M+H]⁺

-   (12)    1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=587 [M+H]⁺

-   (13)    1-[(6-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.45 (silica gel, ethyl acetate/petroleum ether=7:3)

Mass spectrum (ESI⁺): m/z=603 [M+H]⁺

-   (14)    1-[(quinoxalin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=559 [M+H]⁺

-   (15)    1-[(6-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.65 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=588 [M+H]⁺

-   (16)    1-[(6-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.43 (silica gel, methylene chloride/methanol=96:4)

Mass spectrum (ESI⁺): m/z=584 [M+H]⁺

-   (17)    1-{[(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine-   (18)    1-[(7-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.24 (silica gel, ethyl acetate/petroleum ether=1:1)

Mass spectrum (ESI⁺): m/z=576 [M+H]⁺

-   (19)    1-[(8-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.63 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=603 [M+H]⁺

-   (20)    1-[(6-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.47 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=576 [M+H]⁺

-   (21)    1-[2-oxo-2-(2-bromo-phenyl)-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=613, 615 [M+H]⁺

-   (22)    1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=456 [M+H]⁺

-   (23)    1-[(4-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=588 [M+H]⁺

-   (24)    1-[(2-phenyl-pyrimidin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.39 (silica gel, methylene chloride/methanol=96:4)

Mass spectrum (ESI⁺): m/z=585 [M+H]⁺

-   (25)    1-[([1,5]naphthyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.28 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=559 [M+H]⁺

-   (26)    1-[(3-cyano-4-methyl-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=597 [M+H]⁺

-   (27)    1-[(4,5-dimethyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=587 [M+H]⁺

-   (28)    1-[(5-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.42 (silica gel, petroleum ether/ethyl acetate=1:2)

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (29)    1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, methylene chloride/ethyl acetate=1:1)

-   (30)    1-[(4-phenyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.46 (silica gel, ethyl acetate)

-   (31)    1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=580 [M+H]⁺

-   (32)    1-[(1,4-dicyano-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.54 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=607 [M+H]⁺

-   (33)    1-[(6,7-dimethoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.36 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=618 [M+H]⁺

-   (34)    1-[(quinazolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.20 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=559 [M+H]⁺

-   (35)    1-[(4-cyano-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.40 (silica gel, methylene chloride/ethyl acetate=7:3)

Mass spectrum (ESI⁺): m/z=584 [M+H]⁺

-   (36)    1-[(quinazolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.20 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=559 [M+H]⁺

-   (37)    1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/ethyl acetate=7:3)

Mass spectrum (ESI⁺): m/z=532 [M+H]⁺

-   (38)    1-(3-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.58 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=532 [M+H]⁺

-   (39)    1-(4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.61 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=532 [M+H]⁺

-   (40)    1-[(pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=508 [M+H]⁺

-   (41)    1-benzyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=507 [M+H]⁺

-   (42)    1-(4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=537 [M+H]⁺

-   (43)    1-(2-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=541, 543 [M+H]⁺

-   (44)    1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=557 [M+H]⁺

-   (45)    1-(2-cyano-4-bromo-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=610, 612 [M+H]⁺

-   (46)    1-(3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=525 [M+H]⁺

-   (47)    1-(3,5-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=567 [M+H]⁺

-   (48)    1-(2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.85 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=525 [M+H]⁺

-   (49)    1-[(6-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.60 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (50)    1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.60 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (51)    1-(2-cyano-3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=566, 568 [M+H]⁺

-   (52)    1-(4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=525 [M+H]⁺

-   (53)    1-(4-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=541, 543 [M+H]⁺

-   (54)    1-(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

-   (55)    1-(3-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

-   (56)    1-(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=566, 568 [M+H]⁺

-   (57)    1-[(5-methoxycarbonyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=555 [M+H]⁺

-   (58)    1-(2-trifluoromethyl-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=600 [M+H]⁺

-   (59)    1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=557 [M+H]⁺

-   (60)    1-(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=577 [M+H]⁺

-   (61)    1-[(2-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (62)    1-(2-cyano-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=562 [M+H]⁺

-   (63)    1-(2-cyano-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=562 [M+H]⁺

-   (64)    1-(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=537 [M+H]⁺

-   (65)    1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=575 [M+H]⁺

-   (66)    1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.65 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=567 [M+H]⁺

-   (67)    1-(3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=541, 543 [M+H]⁺

-   (68)    1-(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.85 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=575 [M+H]⁺

-   (69)    1-[([2,2′]bipyridinyl-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.53 (aluminium oxide, methylene chloride/methanol=98:2)

Mass spectrum (ESI⁺): m/z=585 [M+H]⁺

-   (70)    1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.65 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=585 [M+H]⁺

-   (71)    1-[(6-fluoro-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=526 [M+H]⁺

-   (72)    1-[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=563 [M+H]⁺

-   (73)    1-(2,6-Difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.62 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=543 [M+H]⁺

-   (74)    1-(3-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.67 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=591 [M+H]⁺

-   (75)    1-(4-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.62 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=591 [M+H]⁺

-   (76)    1-[(2-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.55 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (77)    1-[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.55 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (78)    1-[(pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.60 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=509 [M+H]⁺

-   (79)    1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.60 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=523 [M+H]⁺

-   (80)    1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=537 [M+H]⁺

-   (81)    1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

R_(f) value: 0.55 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=439, 441 [M+H]⁺

-   (82)    1-(3-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=555 [M+H]⁺

-   (83)    1-(3,4-difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.75 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=543 [M+H]⁺

-   (84)    1-(2-fluoro-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.55 (silica gel, ethyl acetate/petroleum ether=3:2)

Mass spectrum (ESI⁺): m/z=555 [M+H]⁺

-   (85)    1-(2-fluoro-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.48 (silica gel, ethyl acetate/petroleum ether=3:2)

Mass spectrum (ESI⁺): m/z=555 [M+H]⁺

-   (86)    1-[(4-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.55 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (87)    1-(2-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.48 (silica gel, ethyl acetate/petroleum ether=1:1)

Mass spectrum (ESI⁺): m/z=555 [M+H]⁺

-   (88)    1-[(furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=497 [M+H]⁺

-   (89)    1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=557 [M+H]⁺

-   (90)    1-(4-cyano-2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

-   (91)    (1-(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

-   (92)    1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=525 [M+H]⁺

-   (93)    1-(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine-   (94)    1-(4-cyano-3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

-   (95)    1-(2-cyano-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

R_(f) value: 0.85 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=442, 444 [M+H]⁺

-   (96)    1-[(8-cyano-quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (97)    1-[(4-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.40 (silica gel, ethyl acetate/cyclohexane=3:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (98)    1-[(8-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.40 (silica gel, ethyl acetate/petroleum ether=4:1)

Mass spectrum (ESI⁺): m/z=583 [M+H]⁺

-   (99)    1-[(1-methyl-1H-benzotriazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.30 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=562 [M+H]⁺

-   (100)    1-[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.30 (silica gel, methylene chloride/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

-   (101)    1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

Mass spectrum (ESI⁺): m/z=413, 415 [M+H]⁺

-   (102)    1-[(4-cyano-benzo[1,3]dioxol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.80 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=576 [M+H]⁺

EXAMPLE II3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

11.00 g of (R)-3-tert.-butyloxycarbonylamino-piperidine are added to15.00 g of 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine and 16.00 gpotassium carbonate in 100 ml dimethylsulfoxide and the thick lightbeige suspension is stirred for four hours with a mechanical stirrer atapprox. 114° C. Then another 900 mg of(R)-3-tert.-butyloxycarbonylamino-piperidine, dissolved in 10 mldimethylsulfoxide, are added to the reaction mixture and this is stirredfor a further two hours at 114° C. After cooling to ambient temperaturethe reaction mixture is liberally diluted with water. The precipitateformed is thoroughly triturated until there are no lumps left andsuction filtered. The light-colored solid is again suspended with water,suction filtered, washed with water and diethyl ether and dried in thecirculating air dryer at 60° C.

Yield: 19.73 g (94% of theory)

R_(f) value: 0.64 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

The following compound is obtained analogously to Example II:

-   (1)    3-methyl-7-(2-butyn-1-yl)-8-[(3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

melting point: 235-237° C.

Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

-   (2)    1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.40 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=559 [M+H]⁺

-   (3)    1-[(5-methyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=511 [M+H]⁺

-   (4)    1-(2-cyano-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=562 [M+H]⁺

-   (5)    1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.50 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=533 [M+H]⁺

EXAMPLE III 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

17.06 g 1-bromo-2-butyn are added to 30.17 g of3-methyl-8-bromo-xanthine and 27.00 ml Hünig base in 370 mlN,N-dimethylformamide. The reaction mixture is stirred for two hours atambient temperature, then another 1 ml of 1-bromo-2-butyne is added andthe mixture is stirred for a further hour at ambient temperature. Forworking up the reaction mixture is diluted with approx. 300 ml water.The light-colored precipitate formed is suction filtered and washed withwater. The filter cake is washed with a little ethanol and diethyl etherand dried at 60° C. in the circulating air dryer.

Yield: 30.50 g (84% of theory)

R_(f) value: 0.24 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=297, 299 [M+H]⁺

EXAMPLE IV 2-chloromethyl-4-phenylamino-quinazoline

Prepared by reacting 500 mg 4-chloro-2-chloromethyl-quinazoline with 438mg aniline in 12 ml methylene chloride at ambient temperature.

Yield: 518 mg (82% of theory)

R_(f) value: 0.60 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=270, 272 [M+H]⁺

The following compound is obtained analogously to Example IV:

-   (1) 2-chloromethyl-4-benzylamino-quinazoline

R_(f) value: 0.60 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=284, 286 [M+H]⁺

EXAMPLE V 1-bromomethyl-4-cyano-isoquinoline

Prepared by bromination of 1-methyl-4-cyano-isoquinoline withN-bromosuccinimide in the presence of azobisisobutyronitrile in carbontetrachloride at 80° C.

R_(f) value: 0.51 (silica gel, methylene chloride)

Mass spectrum (EI): m/z=246, 248 [M]⁺

The following compounds are obtained analogously to Example V:

-   (1) 2-bromomethyl-4-cyano-quinoline

Mass spectrum (ESI⁺): m/z=247, 249 [M+H]⁺

-   (2) 3-bromomethyl-1-cyano-isoquinoline

Mass spectrum (ESI⁺): m/z=247, 249 [M+H]⁺

-   (3) 1-bromomethyl-4-(pyridin-2-yl)-isoquinoline

R_(f) value: 0.47 (silica gel, methylene chloride/methanol=9:1)

-   (4) 2-bromomethyl-4-methoxy-quinoline

Mass spectrum (ESI⁺): m/z=252, 254 [M+H]⁺

-   (5) 3-bromomethyl-[1,5]naphthyridine

Mass spectrum (ESI⁺): m/z=223, 225 [M+H]⁺

-   (6) 2-bromomethyl-5-cyano-quinoline

R_(f) value: 0.28 (silica gel, petroleum ether/ethyl acetate=5:1)

Mass spectrum (ESI⁺): m/z=247, 249 [M+H]⁺

-   (7) 2-bromomethyl-3-cyano-quinoline

R_(f) value: 0.65 (silica gel, cyclohexane/ethyl acetate=3:1)

-   (8) 2-bromomethyl-4-phenyl-pyrimidine

R_(f) value: 0.88 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=249, 251 [M+H]⁺

-   (9) 2-bromomethyl-1,4-dicyano-naphthalene

R_(f) value: 0.48 (silica gel, petroleum ether/ethyl acetate=9:1)

Mass spectrum (EI⁺): m/z=270, 272 [M]⁺

-   (10) 2-bromomethyl-6,7-dimethoxy-quinoline

R_(f) value: 0.70 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=282, 284 [M+H]⁺

-   (11) 2-bromomethyl-4-cyano-quinazoline

R_(f) value: 0.85 (silica gel, methylene chloride/methanol=99:1)

Mass spectrum (EI⁺): m/z=247, 249 [M]⁺

-   (12) 7-bromomethyl-quinazoline

R_(f) value: 0.15 (silica gel, methylene chloride/methanol=99:1)

Mass spectrum (ESI⁺): m/z=223, 225 [M+H]⁺

-   (13) 2-trifluoromethyl-4-cyano-benzylbromide-   (14) 2-bromomethyl-5-cyano-6-methoxy-pyridine

Mass spectrum (ESI⁺): m/z=227, 229 [M+H]⁺

-   (15) 3-bromomethyl-4-cyano-isoquinoline

R_(f) value: 0.43 (silica gel, petroleum ether/ethyl acetate=7:3)

-   (16) 7-bromomethyl-8-cyano-quinoline

R_(f) value: 0.25 (silica gel, petroleum ether/ethyl acetate=7:3)

Mass spectrum (ESI⁺): m/z=247, 249 [M+H]⁺

-   (17) 2-bromomethyl-8-cyano-quinoline

R_(f) value: 0.75 (silica gel, methylene chloride/methanol=99:1)

Mass spectrum (ESI⁺): m/z=247, 249 [M+H]⁺

EXAMPLE VI 2-bromo-1-(3-cyclopropyloxy-phenyl)-ethanone

Prepared by bromination of 1-(3-cyclopropyloxy-phenyl)-ethanone withphenyltrimethylammonium tribromide in methylene chloride at refluxtemperature.

R_(f) value: 0.75 (silica gel, cyclohexane/ethyl acetate=3:1)

Mass spectrum (ESI⁺): m/z=255, 257 [M+H]⁺

The following compounds are obtained analogously to Example VI:

-   (1) 2-bromo-1-(3-cyclopropylmethoxy-phenyl)-ethanone

R_(f) value: 0.70 (silica gel, cyclohexane/ethyl acetate=3:1)

-   (2) 2-bromo-1-(3-cyclobutyloxy-phenyl)-ethanone

R_(f) value: 0.70 (silica gel, cyclohexane/ethyl acetate=3:1)

EXAMPLE VII 1-(3-cyclopropyloxy-phenyl)-ethanone

Prepared by reacting 3-hydroxyacetophenone with bromocyclopropane in thepresence of potassium iodide and potassium-tert.butoxide inN,N-dimethylformamide in the microwave at 220° C.

R_(f) value: 0.65 (silica gel, cyclohexane/ethyl acetate=3:1)

Mass spectrum (ESI⁺): m/z=177 [M+H]⁺

The following compounds are obtained analogously to Example VII:

-   (1) 1-(3-cyclopropylmethoxy-phenyl)-ethanone

R_(f) value: 0.70 (silica gel, cyclohexane/ethyl acetate=3:1)

Mass spectrum (ESI⁺): m/z=191 [M+H]⁺

-   (2) 1-(3-cyclobutyloxy-phenyl)-ethanone

R_(f) value: 0.65 (silica gel, cyclohexane/ethyl acetate=3:1)

Mass spectrum (ESI⁺): m/z=191 [M+H]⁺

EXAMPLE VIII 1-chloromethyl-2,4-dimethoxy-naphthalene

Prepared by chlorinating 1-hydroxymethyl-2,4-dimethoxy-naphthalene withthionyl chloride in methylene chloride at ambient temperature.

R_(f) value: 0.78 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (EI): m/z=236, 238 [M]⁺

EXAMPLE IX 1-hydroxymethyl-2,4-dimethoxy-naphthalene

Prepared by reducing 2,4-dimethoxy-naphthalene-1-carboxaldehyde withsodium borohydride in a mixture of dioxane and water (3:1) at ambienttemperature.

R_(f) value: 0.48 (silica gel, cyclohexane/ethyl acetate=1:1)

EXAMPLE X 1-[(6-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by treating1-[(6-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith sodium dithionite in a mixture of ethanol/water (5:2) at 55-60° C.

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=573 [M+H]⁺

EXAMPLE XI 1-methyl-4-(pyridin-2-yl)-isoquinoline

Prepared by reacting 4-bromo-1-methyl-isoquinoline withlithium-triisopropoxy-2-pyridinyl-boronate in the presence oftetrakis(triphenylphosphine)palladium, triphenylphosphine, sodiumcarbonate, and copper(I)iodide in 1,4-dioxane at reflux temperature.

R_(f) value: 0.22 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=221 [M+H]⁺

EXAMPLE XII1-[(8-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by treating1-[(8-nitro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith iron powder in a mixture of glacial acetic acid, ethanol and water(2:20:5) at reflux temperature.

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=95:5)

Mass spectrum (ESI⁺): m/z=573 [M+H]⁺

EXAMPLE XIII1-{2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by reacting1-[2-oxo-2-(2-bromo-phenyl)-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith pyridine-3-boric acid in the presence oftetrakis(triphenylphosphine)palladium, tetra-n-butylammonium bromide andsodium carbonate in a mixture of toluene/ethanol (1:1) at 105° C.

R_(f) value: 0.55 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=612 [M+H]⁺

The following compound is obtained analogously to Example XII:

-   (1)    1-{2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

(The reaction is carried out with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine).

R_(f) value: 0.40 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=612 [M+H]⁺

EXAMPLE XIV1-[(4-ethyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by treating1-cyanomethyl-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith potassium-tert.-butoxide in methanol and subsequently reacting theresulting iminoester with 2-amino-propiophenone in the presence ofglacial acetic acid.

R_(f) value: 0.60 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=587 [M+H]⁺

The following compound is obtained analogously to Example XIV:

-   (1)    1-[(4-cyclopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

R_(f) value: 0.70 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=599 [M+H]⁺

EXAMPLE XV 2-chloromethyl-3-cyano-4-methyl-quinoline

Prepared by reacting 3-cyano-2,4-dimethyl-1-oxy-quinoline withbenzosulfonic acid chloride in toluene at 80° C.

R_(f) value: 0.55 (silica gel, cyclohexane/ethyl acetate=2:1)

Mass spectrum (ESI⁺): m/z=217, 219 [M+H]⁺

EXAMPLE XVI 3-cyano-2,4-dimethyl-1-oxy-quinoline

Prepared by treating 3-cyano-2,4-dimethyl-quinoline with aqueoushydrogen peroxide solution (35%) in glacial acetic acid at 60° C.

R_(f) value: 0.35 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=199 [M+H]⁺

EXAMPLE XVII 2-chloromethyl-4,5-dimethyl-quinazoline

Prepared by reacting 1-(2-amino-6-methyl-phenyl)-ethanone withchloroacetonitrile in dioxane while piping in hydrogen chloride at30-38° C.

Mass spectrum (ESI⁺): m/z=207, 209 [M+H]⁺

EXAMPLE XVIII1-[(2-methyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by reacting1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith ethanolic ammonia (6 M) and ammonium chloride in the autoclave at150° C.

R_(f) value: 0.35 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=573 [M+H]⁺

EXAMPLE XIX1-[2-(2-acetylamino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by reacting1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith acetyl chloride in the presence of pyridine in methylene chlorideat ambient temperature.

R_(f) value: 0.79 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=592 [M+H]⁺

EXAMPLE XX1-[2-(2-amino-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine

Prepared by reducing1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith tin(II)chloride dihydrate in tetrahydrofuran at ambienttemperature.

R_(f) value: 0.85 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

EXAMPLE XXI1-[(furan-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine

A mixture of 300 mg of3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine,95 μl furan-3-yl-methanol, 302 mg triphenylphosphine and 226 μldiisopropyl azodicarboxylate in 4 ml tetrahydrofuran is stirredovernight at ambient temperature. For working up the reaction mixture iscombined with saturated potassium carbonate solution and extracted withethyl acetate. The combined organic phases are dried over magnesiumsulfate and evaporated down. The flask residue is chromatographed over asilica gel column with cyclohexane/ethyl acetate (1:1 to 3:7).

Yield: 330 mg (92% of theory)

Mass spectrum (ESI⁺): m/z=497 [M+H]⁺

The following compounds are obtained analogously to Example XXI:

-   (1)    1-[(5-methyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

Mass spectrum (ESI⁺): m/z=391, 393 [M+H]⁺

-   (2)    1-[(5-bromo-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

Mass spectrum (ESI⁺): m/z=575, 577 [M+H]⁺

EXAMPLE XXII1-[(5-cyano-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxy-carbonylamino)-piperidin-1-yl]-xanthine

Prepared by reacting1-[(5-formyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinewith hydroxylamine-O-sulfonic acid and pyridine in toluene at refluxtemperature.

EXAMPLE XXIII 5-(methanesulfonyloxymethyl)-2-furan-carboxaldehyde

Prepared by reacting 5-(hydroxymethyl)-2-furan-carboxaldehyde withmethanesulfonic acid chloride in the presence of triethylamine inmethylene chloride at ambient temperature. The crude product is furtherreacted without any more purification.

EXAMPLE XXIV 2-chloromethyl-3-cyano-pyridine

Prepared from 2-(hydroxymethyl)-nicotinamide by reaction with thionylchloride in acetonitrile and subsequent dehydration of the2-(chloromethyl)-nicotinamide thus obtained with trifluoroacetic acidanhydride in the presence of triethylamine in methylene chloride.

Alternatively the compound is also obtained in one step by refluxing2-(hydroxy-methyl)-nicotinamide with phosphorus oxychloride.

R_(f) value: 0.85 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=153, 155 [M+H]⁺

EXAMPLE XXV 8-cyano-7-methyl-quinoline

Prepared by reacting 8-bromo-7-methyl-quinoline with zinc cyanide in thepresence of tetrakis(triphenylphosphine)palladium inN-methylpyrrolidinone under a protective gas atmosphere at 100-105° C.

R_(f) value: 0.35 (silica gel, petroleum ether/ethyl acetate=7:3)

Mass spectrum (ESI⁺): m/z=169 [M+H]⁺

EXAMPLE XXVI 2-methyl-8-cyano-quinoline

Prepared by reacting 2-methyl-8-bromo-quinoline with copper(I)cyanide inN-methylpyrrolidinone under a protective gas atmosphere at 180° C.

R_(f) value: 0.40 (silica gel, petroleum ether/ethyl acetate=7:3)

Mass spectrum (ESI⁺): m/z=169 [M+H]⁺

Preparation of the Final Compounds

EXAMPLE 11-[(4-phenylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

A mixture of 400 mg1-[(4-phenylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthinein 10 ml methylene chloride is combined with 2 ml isopropanolichydrochloric acid (5-6 M) and stirred for three hours at ambienttemperature. Then the reaction mixture is diluted with methylenechloride, combined with ice water and made alkaline with 3 M potassiumcarbonate solution. The aqueous phase is extracted with methylenechloride. The combined extracts are washed with water, dried overmagnesium sulfate and evaporated down. The flask residue is stirred withdiethyl ether, suction filtered, washed with diethyl ether and dried invacuo.

Yield: 274 mg (81% of theory)

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=550 [M+H]⁺

The following compounds are obtained analogously to Example 1:

-   (1)    1-[(4-benzylamino-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=564 [M+H]⁺

-   (2)    1-[(2-methyl-quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

Mass spectrum (ESI⁺): m/z=472 [M+H]⁺

-   (3)    1-[(3-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=482 [M+H]⁺

-   (4)    1-[(2-phenyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.45 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=535 [M+H]⁺

-   (5)    1-[(4-cyano-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.15 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (6)    1-[(4-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (7)    1-[2-(3-cyclopropyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.45 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=491 [M+H]⁺

-   (8)    1-[2-(3-cyclopropylmethoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.35 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=505 [M+H]⁺

-   (9)    1-[2-(3-cyclobutyloxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.40 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=505 [M+H]⁺

-   (10)    1-[(1-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (11)    1-[(2,4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.55 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=517 [M+H]⁺

-   (12)    1-[(2,3-dimethyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=487 [M+H]⁺

-   (13)    1-[(6-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=473 [M+H]⁺

-   (14)    1-[(quinoxalin-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-hydrochloride

Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

-   (15)    1-[(6-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=488 [M+H]⁺

-   (16)    1-[(6-phenyl-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=484 [M+H]⁺

-   (17)    1-{[(4-(pyridin-2-yl)-isoquinolin-1-yl]methyl}-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueousammonia=80:20:1)

Mass spectrum (ESI⁺): m/z=535 [M+H]⁺

-   (18)    1-[(7-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.58 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=476 [M+H]⁺

-   (19)    1-[(8-amino-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=473 [M+H]⁺

-   (20)    1-[(6-fluoro-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=476 [M+H]⁺

-   (21)    1-{2-oxo-2-[2-(pyridin-3-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.55 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=512 [M+H]⁺

-   (22)    1-[(4-ethyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=487 [M+H]⁺

-   (23)    1-[(4-cyclopropyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=499 [M+H]⁺

-   (24)    1-[(4-methoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

Mass spectrum (ESI⁺): m/z=488 [M+H]⁺

-   (25)    1-[(2-phenyl-pyrimidin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=485 [M+H]⁺

-   (26)    1-[([1,5]naphthyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

-   (27)    1-[(3-cyano-4-methyl-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=497 [M+H]⁺

-   (28)    1-[(4,5-dimethyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=487 [M+H]⁺

-   (29)    1-[(5-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (30)    1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (31)    1-[(4-phenyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=485 [M+H]⁺

-   (32)    1-[(2-methyl-quinazolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=473 [M+H]⁺

-   (33)    1-[(1,4-dicyano-naphthalen-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-hydrochloride

R_(f) value: 0.86 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=507 [M+H]⁺

-   (34)    1-{2-oxo-2-[2-(pyridin-4-yl)-phenyl]-ethyl}-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.55 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=512 [M+H]⁺

-   (35)    1-[(6,7-dimethoxy-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=518 [M+H]⁺

-   (36)    1-[(quinazolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-hydrochloride

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

-   (37)    1-[(4-cyano-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=484 [M+H]⁺

-   (38)    1-[(quinazolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

-   (39)    1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.35 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=432 [M+H]⁺

-   (40)    1-(3-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=432 [M+H]⁺

-   (41)    1-(4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=432 [M+H]⁺

-   (42)    1-[(pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.52 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=408 [M+H]⁺

-   (43)    1-benzyl-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

melting point: 207-209° C.

Mass spectrum (ESI⁺): m/z=407 [M+H]⁺

-   (44)    1-(4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-hydrochloride

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=437 [M+H]⁺

-   (45)    1-(2-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=441, 443 [M+H]⁺

-   (46)    1-(2,6-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=457 [M+H]⁺

-   (47)    1-(2-cyano-4-bromo-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=510, 512 [M+H]⁺

-   (48)    1-(3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=425 [M+H]⁺

-   (49)    1-(3,5-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=467 [M+H]⁺

-   (50)    1-(2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=425 [M+H]⁺

-   (51)    1-[(6-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (52)    1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (53)    1-(2-cyano-3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=466, 468 [M+H]⁺

-   (54)    1-(4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=425 [M+H]⁺

-   (55)    1-(4-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=441, 443 [M+H]⁺

-   (56)    1-(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

-   (57)    1-(3-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

-   (58)    1-(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=466, 468 [M+H]⁺

-   (59)    1-[(5-methoxycarbonyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=455 [M+H]⁺

-   (60)    1-(2-trifluoromethyl-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=500 [M+H]⁺

-   (61)    1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=457 [M+H]⁺

-   (62)    1-(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=477 [M+H]⁺

-   (63)    1-[(2-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (64)    1-(2-cyano-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=462 [M+H]⁺

-   (65)    1-(2-cyano-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=462 [M+H]⁺

-   (66)    1-(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=437 [M+H]⁺

-   (67)    1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.60 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=475 [M+H]⁺

-   (68)    1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=467 [M+H]⁺

-   (69)    1-(3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=441, 443 [M+H]⁺

-   (70)    1-(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=475 [M+H]⁺

-   (71)    1-[([2,2′]bipyridinyl-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=485 [M+H]⁺

-   (72)    1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=485 [M+H]⁺

-   (73)    1-[(6-fluoro-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=426 [M+H]⁺

-   (74)    1-[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=463 [M+H]⁺

-   (75)    1-(2,6-difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=443 [M+H]⁺

-   (76)    1-(3-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.36 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=491 [M+H]⁺

-   (77)    1-(4-trifluoromethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.38 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=491 [M+H]⁺

-   (78)    1-[(2-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.60 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (79)    1-[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.60 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (80)    1-[(pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.60 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=409 [M+H]⁺

-   (81)    1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.65 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=423 [M+H]⁺

-   (82)    1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

melting point: 202-204° C.

Mass spectrum (ESI⁺): m/z=437 [M+H]⁺

-   (83)    1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

-   (84)    1-(3-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=455 [M+H]⁺

-   (85)    1-(3,4-difluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=443 [M+H]⁺

-   (86)    1-(2-fluoro-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.39 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=455 [M+H]⁺

-   (87)    1-(2-fluoro-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.41 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=455 [M+H]⁺

-   (88)    1-[(4-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (89)    1-(2-fluoro-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=455 [M+H]⁺

-   (90)    1-[(furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=397 [M+H]⁺

-   (91)    1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=457 [M+H]⁺

-   (92)    1-[(furan-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=397 [M+H]⁺

-   (93)    1-[(5-methyl-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=411 [M+H]⁺

-   (94)    1-[(5-bromo-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=475, 477 [M+H]⁺

-   (95)    1-(4-cyano-2-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

-   (96)    1-(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

-   (97)    1-[(5-cyano-furan-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=422 [M+H]⁺

-   (98)    1-(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

-   (99)    1-(4-cyano-3-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

-   (100)    1-(2-cyano-3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=462 [M+H]⁺

-   (101)    1-[(8-cyano-quinolin-7-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (102)    1-[(4-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

melting point: 166° C.

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (103)    1-[(8-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.50 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=483 [M+H]⁺

-   (104)    1-[(1-methyl-1H-benzotriazol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.60 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=462 [M+H]⁺

-   (105)    1-[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    x trifluoroacetic acid

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.65 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (106)    1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine

(BOC cleaving carried out with trifluoroacetic acid)

R_(f) value: 0.60 (reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=433 [M+H]⁺

-   (107)    1-[(4-cyano-benzo[1,3]dioxol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

R_(f) value: 0.45 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:0.1)

Mass spectrum (ESI⁺): m/z=476 [M+H]⁺

The following compounds may also be obtained analogously to theforegoing Examples and other methods known from the literature:

-   (1)    1-(2-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (2)    1-(2-cyano-5-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (3)    1-(2-cyano-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (4)    1-(3-cyano-4-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (5)    1-(3,5-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (6)    1-(3,4-dicyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (7)    1-(3-nitro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (8)    1-(2-chloro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (9)    1-(2-fluoro-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (10)    1-(2-trifluoromethyl-4-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (11)    1-[(5-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (12)    1-[(4-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (13)    1-[(4-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (14)    1-[(3-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (15)    1-[(2-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (16)    1-[(2-cyano-pyridin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (17)    1-[(5-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (18)    1-[(6-cyano-pyridin-3-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (19)    1-(2-cyano-4-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (20)    1-(2-cyano-5-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (21)    1-[([2,2′]bipyridinyl-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (22)    1-[(5-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (23)    1-[(6-fluoro-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (24)    1-[(5-cyano-6-methoxy-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (25)    1-(2-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (26)    1-(3-methoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (27)    1-(3-chloro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (28)    1-(4-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (29)    1-(3-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (30)    1-(2-trifluoromethyl-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (31)    1-(3,4-dimethoxy-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (32)    1-(3,4-dimethoxy-6-fluoro-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine-   (33)    1-[(benzo[1,3]dioxol-5-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine

EXAMPLE 2 Coated Tablets Containing 75 mg of Active Substance

1 tablet core contains:

active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mgpolyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mgmagnesium stearate  1.5 mg 230.0 mg 

Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks about 13 mm in diameterare produced in a tablet-making machine and these are then rubbedthrough a screen with a mesh size of 1.5 mm using a suitable machine andmixed with the rest of the magnesium stearate. This granulate iscompressed in a tablet-making machine to form tablets of the desiredshape.

Weight of core: 230 mg Die: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.

EXAMPLE 3 Tablets Containing 100 mg of Active Substance

Composition:

1 tablet contains:

active substance 100.0 mg lactose  80.0 mg corn starch  34.0 mgpolyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg 220.0 mg

Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on bothsides and notched on one side.

EXAMPLE 4 Tablets Containing 150 mg of Active Substance

Composition:

1 tablet contains:

active substance 150.0 mg  powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg 

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

Weight of tablet: 300 mg Die: 10 mm, flat

EXAMPLE 5 Hard Gelatine Capsules Containing 150 mg of Active Substance

1 capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose(powdered) approx.  87.0 mg magnesium stearate  3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatinecapsule.

EXAMPLE 6 Suppositories Containing 150 mg of Active Substance

1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2,000.0 mg  

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE 7 Suspension Containing 50 mg of Active Substance

100 ml of suspension contain:

active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methylp-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 gglycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist.water ad 100 ml

Preparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavoring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contains 50 mg of active substance.

EXAMPLE 8 Ampoules Containing 10 mg Active Substance

Composition:

active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilledwater ad 2.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

EXAMPLE 9 Ampoules Containing 50 mg of Active Substance

Composition:

active substance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilledwater ad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

1. A compound of the formula (I):

wherein R denotes: a benzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2,6-difluoro-benzyl, 3,4-difluoro-benzyl,2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or4-trifluoromethyl-benzyl group, a 3-trifluoromethoxy-benzyl or4-trifluoromethoxy-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or4-cyanobenzyl group, a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl,3,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl,3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl,2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl,2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl,2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl,4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl,2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzylgroup, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl,2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl,2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl,3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or3,4-dimethoxy-6-fluoro-benzyl group, a (furan-2-yl)methyl,(furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl,(5-methyl-furan-2-yl)methyl, (5-cyano-furan-2-yl)methyl or(5-methoxycarbonyl-furan-2-yl)methyl group, a (pyridin-2-yl)methyl,(6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group, a(3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl,(5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl,(4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl,(2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl,(5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or(5-cyano-6-methoxy-pyridin-2-yl)methyl group, a(6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl group,a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or(4,6-dimethyl-pyrimidin-2-yl)methyl group, or a(2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methylgroup, or diastereomer thereof, or a mixture thereof, or a salt thereof.2. A compound of the formula (Ia):

wherein R denotes: a benzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2,6-difluoro-benzyl, 3,4-difluoro-benzyl,2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or4-trifluoromethyl-benzyl group, a 3-trifluoromethoxy-benzyl or4-trifluoromethoxy-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or4-cyanobenzyl group, a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl,3,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl,3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl,2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl,2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl,2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl,4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl,2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzylgroup, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl,2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl,2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl,3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or3,4-dimethoxy-6-fluoro-benzyl group, a (furan-2-yl)methyl,(furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl,(5-methyl-furan-2-yl)methyl, (5-cyano-furan-2-yl)methyl or(5-methoxycarbonyl-furan-2-yl)methyl group, a (pyridin-2-yl)methyl,(6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group, a(3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl,(5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl,(4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl,(2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl,(5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or(5-cyano-6-methoxy-pyridin-2-yl)methyl group, a(6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl group,a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or(4,6-dimethyl-pyrimidin-2-yl)methyl group, or a(2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methylgroup, or a tautomer or salt thereof.
 3. A compound of the formula (Ib):

wherein R denotes: a benzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2,6-difluoro-benzyl, 3,4-difluoro-benzyl,2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group, a2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or4-trifluoromethyl-benzyl group, a 3-trifluoromethoxy-benzyl or4-trifluoromethoxy-benzyl group, a 2-cyanobenzyl, 3-cyanobenzyl or4-cyanobenzyl group, a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl,3,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl,3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl,2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl,2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl,2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl,4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl,2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzylgroup, a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl,2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl,2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl,3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or3,4-dimethoxy-6-fluoro-benzyl group, a (furan-2-yl)methyl,(furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl,(5-methyl-furan-2-yl)methyl, (5-cyano-furan-2-yl)methyl or(5-methoxycarbonyl-furan-2-yl)methyl group, a (pyridin-2-yl)methyl,(6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group, a(3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl,(5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl,(4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl,(2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl,(5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or(5-cyano-6-methoxy-pyridin-2-yl)methyl group, a(6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl group,a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or(4,6-dimethyl-pyrimidin-2-yl)methyl group, or a(2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methylgroup, or a tautomer or salt thereof.
 4. A physiologically acceptablesalt of the compound according to claim 1, with inorganic or organicacids.
 5. A physiologically acceptable salt of the compound according toclaim 2, with inorganic or organic acids.
 6. A physiologicallyacceptable salt of the compound according to claim 3, with inorganic ororganic acids.
 7. A pharmaceutical composition comprising a compoundaccording to claim 1, with one or more inert carriers or diluents.
 8. Apharmaceutical composition comprising a compound according to claim 2,with one or more inert carriers or diluents.
 9. A pharmaceuticalcomposition comprising a compound according to claim 3, with one or moreinert carriers or diluents.
 10. A method of treating type II diabetesmellitus or obesity, comprising administering to a patient apharmaceutically effective amount of a compound according to claim 1.11. A method of treating type II diabetes mellitus or obesity,comprising administering to a patient a pharmaceutically effectiveamount of a compound according to claim
 2. 12. A method of treating typeII diabetes mellitus or obesity, comprising administering to a patient apharmaceutically effective amount of a compound according to claim 3.13. A compound of the formula (Ia) or a physiologically acceptable saltthereof with an inorganic or organic acid

wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
 14. Apharmaceutical composition comprising one or more inert carriers ordiluents and a compound of the formula (Ia) or a physiologicallyacceptable salt thereof with an inorganic or organic acid

wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
 15. A method oftreating type II diabetes mellitus or obesity, comprising the step ofadministering to a patient a pharmaceutically effective amount of acompound of the formula (Ia) or a physiologically acceptable saltthereof with an inorganic or organic acid

wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
 16. A method oftreating type II diabetes mellitus comprising the step of administeringto a patient a pharmaceutically effective amount of a compound of theformula (Ia) or a physiologically acceptable salt thereof with aninorganic or organic acid

wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
 17. The compound1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthinein a physiologically acceptable salt form with an inorganic or organicacid.
 18. A pharmaceutical composition comprising one or more inertcarriers or diluents and1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthinein a physiologically acceptable salt form with an inorganic or organicacid.
 19. A method of treating type II diabetes mellitus or obesity,comprising the step of administering to a patient a pharmaceuticallyeffective amount of1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthinein a physiologically acceptable salt form with an inorganic or organicacid.
 20. A method of treating type II diabetes mellitus comprising thestep of administering to a patient a pharmaceutically effective amountof1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthinein a physiologically acceptable salt form with an inorganic or organicacid.